Opioids are classified as natural opioid (e.g., morphine and codeine noscopine), semi-synthetic opioid (e.g., heroin, oxymorphone, and hydromorphone), synthetic opioid (e.g., methadone, morphinians, and benzamorphans), and peptides opioid (e.g. endorphins, enkephalins and dynorphins).
It is well known in the art that opioids act in both the central and peripheral nervous systems to produce various pharmacological effects, including analgesia, drowsiness, mood changes, respiratory depression, dizziness, mental clouding, dysphoria pruritus, nausea, vomiting, increased pressure in the biliary tract, decreased gastrointestinal motility, and alteration of the endocrine or autonomic nervous systems. They have long been the most potent and effective analgesics available to treat acute pain (such as post-operative pain) and chronic and disabling pain (such as pain from cancer).
Opioids primarily activate three classic subtypes of opioid receptors, namely, mu-opioid receptor (MOR), delta-opioid receptor (DOR), and kappa-opioid receptor (KOR), to exert therapeutic effects. These opioid receptors are all G-protein-coupled receptors. Most opioids clinically used as analgesics produce undesired effects, e.g., respiratory depression. Furthermore, long-term use of opioids for controlling chronic pain develops severe side effects, e.g., tolerance, dependence, and addiction.
There is a need to develop new opioids that modulate opioid receptors with fewer side effects for the treatment of opioid receptor-associated conditions, e.g., pain, immune function, and esophageal reflux.